Cost-utility and cost-effectiveness analysis of disease-modifying drugs of relapsing–remitting multiple sclerosis: a systematic review

Background Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease. The economic burden of MS is substantial, and the high cost of Disease-modifying drugs (DMDs) prices are the main drivers of healthcare expenditures. We conducted a systematic review of studies evaluating the cost-utility and cost-effectiveness of DMDs for relapsing–remitting multiple sclerosis (RRMS). Materials and method Searches were conducted in PubMed, Web of Science, Scopus, and Embase. The search covered articles published between May 2001 and May 2023. Studies that were written in English and Persian and examined the cost-utility and cost-effectiveness of DMDs in patients with MS were included in our review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, and the quality of economic evaluations was assessed using the Quality of Health Economics Studies Instrument (QHES). All costs were converted to 2020 U.S. dollars using Purchasing Power Parity (PPP). Results The search yielded 1589 studies, and 49 studies were eligible for inclusion. The studies were mainly based on a European setting. Most studies employed Markov model to assess the cost–effectiveness. The lowest and highest numerical value of outcome measures were -1,623,918 and 2,297,141.53, respectively. Furthermore, the lowest and highest numerical value of the cost of DMDs of RRMS were $180.67, and $1474840.19, respectively. Conclusions Based on the results of all studies, it can be concluded that for the treatment of patients with MS, care-oriented strategies should be preferred to drug strategies. Also, among the drug strategies with different prescribing methods, oral disease-modifying drugs of RRMS should be preferred to injectable drugs and intravenous infusions. Supplementary Information The online version contains supplementary material available at 10.1186/s13561-024-00478-7.


Introduction
MS is a chronic demyelinating disorder of the central nervous system that is clasified as an immune-mediated inflammatory disease [1,2].The clinical course and severity of the disease are variable, but the most common symptoms of the disease include paralysis, tingling, weakness, impaired balance and gait, blurred vision or diplopia, vertigo, cognitive impairment, fatigue, and urinary bladder dysfunction [3].The prevalence of MS has increased in many parts of the world since 2013.The number of patients with MS has increased from 2.3 million in 2013 to 2.8 million in 2020 [4].A meta-analysis study in 2020 indicated that the annual prevalence of MS had increased by 2.3% in the span of 1985-2018 [5].The disease usually occurs between 20-50 years of age and women are twice as likely to have MS as men [6].
The course of MS is divided into four types: progressive-relapsing MS (PRMS), RRMS, primary progressive MS (PPMS), and secondary progressive MS (SPMS) [7].RRMS, the most common form of MS is marked by worsening of neurological symptoms or unpredictable relapses, (also knwn as exacerbations and attacks).A relapse is followed by a remission.During a remission, symptoms partly or completely go away [8].About 85% of people with MS are initially diagnosed with RRMS, which is characterized by destructive attacks on neurigical function, followed by periods of remission, and without progression of the disease.Approximately 50% of patients with MS will eventually transition to SPMS.This transmission is characterized by progressive worsening of the disease [9].SPMS affects women twice as often as men [7].Relapse and disability level are associated with a higher risk for mortality, additional costs, and quality of life (QoL) losses [10].
There are several pharmacological treatments for RRMS.These disease-modifying therapies (DMTs) can reduce the number of relapses, stop or slow the progression of residual disability [10] and delay the progression of the disease but contribute to increased treatment costs [11].The main goal of different MS treatments is to prevent or delay long-term disabilities.There is currently no definitive cure for MS, but various drugs are being used to control the disease, amongst which are interferon beta and glatiramer acetate, oral drugs (dimethyl fumarate (DMF), teriflunomide and fingolimod), natalizumab and alemtuzumab [12].
MS imposes a substantial economic burden on the healthcare system, patients, caregivers, and society as a whole because of its chronic progressive disease course [13].The annual healthcare cost per MS patient increased from $ 45,471 in 2011 to $ 62,500 in 2015.In addition, the annual cost of purchasing medication for each MS patient increased from $ 26,772 to $ 43,606 during the same period [14].The costs of DMDs account for a large proportion of total medical costs (64% to 91%) [15].A study in Spain indicated that the total cost of MS was € 1395 million per year, with an average annual cost of € 30,050 per patient.In addition to the costs, the disease significantly impacts patients' QoL, and MS caused a loss of 13,000 quality-adjusted life years (QALYs) annually [16].
A study in France in 2016 estimated the incremental cost-effectiveness ratio (ICER) for delayed-release DMF versus relevant MSDMTs available and demonstrated from both the payer and societal perspectives DMF and IFN beta-1a 44 mcg were the two dominant treatments.IFN beta-1a 30 mcg, IFN beta-1b 250 mcg, teriflunomide, glatiramer acetate, fingolimod were dominated on the efficiency frontier.From the societal perspective, DMF versus IFN beta-1a 44 mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY [17].A study in the US demonstrated that over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and an additional 0.06 QALYs compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained compared with glatiramer acetate 20 mg [18].A study in 2022 estimated the effectiveness and cost-effectiveness of 360 treatment sequences in RRMS using a microsimulation model from a societal perspective.In this study, the most effective treatment sequence was peginterferon, followed by DMF for patients were at first-line treatment.Patients with relapse or Expanded Disability Status Scale (EDSS) progression on either peginterferon or DMF were then switched to second-line treatment ocrelizumab, then natalizumab, and finally third-line treatment alemtuzumab.This sequence yielded 20.24 ± 1.43 QALYs.Also, the most cost-effective sequence (peginterferon, glatiramer acetate, ocrelizumab, cladribine, and alemtuzumab) yielded 19.59 ± 1.43 QALYs [19].
Given the increasing number of MS patients and available DMTs, and the considerable economic burden associated with MS, it is impoertant to identify which treatment options are most cost-effective.The cost-utility and cost-effectiveness of different oral and injectable DMTs has been evaluated in previous studies, but costutility and cost-effectiveness analysis of RRMS treatment sistematically has not yet been put forward in a single study.Starting from this point, we aim to fill the gap in the literature by conducting a systematic review to analyze cost-utility and cost-effectiveness of DMDs for RRMS.For this purpose, the present study aimed to analyze the cost-utility and cost-effectiveness of relapsingremitting drugs for MS.

Study design
A systematic review was conducted in accordance with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 24-item checklist [20].

Search strategy
We searched Pubmed, Web of Science, Scopus, and Embase databases for eligible studies published until August 2023.The search covered eligible articles published between May 2001 and May 2023.The search of all databases was initially conducted in January 2020 and was updated in August 2023.The search was conducted using combinations of Medical Subject Heading (MeSH) terms for "Disease-Modifying Drugs, Relapsing-Remitting Multiple Sclerosis, Cost-Utility Analysis, Cost-Effectiveness Analysis" to retrieve potentially relevant publications (Additional file 1).Additionally, we searched on Google Scholar based on keywords and examined the reference lists of included articles and grey literatures for additional relevant articles.The search procedure was completed with hand searching.

Eligibility criteria
The articles included in this review met the Population, Intervention, Comparison, and Outcome (PICOS) criteria contained in WHO guidelines: P: The population comprised patients with MS and taking the drugs for RRMS; I: The intervention comprised DMDs of RRMS; C: The comparison included using other types of drug and treatment methods (if could be substituted); O: Outcomes measure included ICER and costs per natural unit of health measurement; S: Studies employed economic evaluation.In our review, the articles were included if they: (1) published until August 2023 and estimated the cost-utility and cost-effectiveness of DMDs for patients with RRMS.Studies were excluded if they were (1) review, conference abstracts, protocols, letters to the editor, (2) were not published in English and Persian languages, (3) if their full text was not available, and (4) and they did not conduct an original economic evaluation (e.g.effectiveness evaluation, cost evaluation).

Study selection
After duplicate articles were removed using EndNote software, two reviewers (NAG & MKH) independently reviewed the title and abstract of all articles obtained from the literature searches for eligibility and discussed when discrepancies arose.Next, two reviewers (NAG & MKH) independently evaluated the full-text articles of all identified citations to establish relevance of the article according to the prespecified criteria.In the case of disagreement in the selection process, any discord was resolved by discussion with a third reviewer (NM).

Data extraction
NM, SS, AE, SH and SS extracted data, and NAG and MKH checked the extracted data.For each study that met the selection criteria, details extracted included the first author's name, year of publication, outcome measure, setting, study population, interventions, type of economic evaluation, perspective, time horizon, willingness to pay (WTP) threshold, discount rate, sensitivity analyses, etc.All costs were converted to 2020 U.S. dollars using Purchasing Power Parity (PPP).

Quality assessment
Quality assessment was done using the Quality of Health Economics Studies Instrument (QHES).QHES is a validated quality-scoring instrument (score range = 0-100; > 75 = high quality), and a practical quantitative tool which widely used in quality appraisal of cost-effectiveness studies [21].Using this tool, studies are graded on whether they provide relevant information that is standard to reporting in economic evaluations, such as an explicit statement of the main objective, specify the inclusion and exclusion criteria, the information sources etc.The tool gives weighting scores to different quality indicators (Table 1).In this review the quality scoring was conducted independently by the first and second authors, and then compared for agreement.Disagreements were resolved through subsequent discussions.The agreement on scoring was 77%.

Study selection
As shown in Fig. 1, the literature search yielded 1589 articles.After the removal of duplicates, titles and abstracts of 549 articles were screened, and 376 irrelevant articles were excluded.Additionally, a further 5 relevant articles were identified by hand searching.A total of 178 articles were selected for full-text evaluation, of which 129 were excluded because they did not meet one or more of the inclusion criteria.Finally, 49 articles met eligibility criteria and were included in our review.

Characteristics of included studies
Of the included studies, twenty-four studies were carried out in European countries, seven in the United States, four in Canada, six in Iran, four in Saudi Arabia, one in Thailand, one in Colombia, one in Chile, and one in Lebanon.Thirteen studies conducted CEA using a Markov model [18,[22][23][24][25][26][27][28][29][30][31][32][33][34], eight studies conducted CUA using a Markov model [35][36][37][38][39][40][41][42], one study conducted CUA Were the perspective of the analysis (health system, third-party payer, etc.) and reason for its selection stated? 3 Were variable estimates used in the analysis from the best available source (i.e.randomized control trial-best, expert opinion-worst)? 4 If estimates came from a subgroup analysis, were the groups prespecified at the beginning of the study?

5
Was uncertainty handled by: (1) statistical analysis to address random events; (2) sensitivity analysis to cover a range of assumptions? 6 Was incremental analysis performed between alternatives for resources and costs? 7 Was the methodology for data abstraction (including the value of health states and other benefits) stated?
8 Did the analytic horizon allow time for all relevant and important outcomes?Were benefits and cost that went beyond 1 year discounted and a justification given for the discount rate? 9 Was the measurement of costs appropriate and the methodology for the estimation of quantities and unit costs clearly described?
10 Were the primary outcome measure(s) for the economic evaluation clearly stated and were the major short-term, long-term, and negative outcomes included?
11 Were the health outcomes measures/scales valid and reliable?If previously tested, valid and reliable measures were not available, was justification given for the measures/scale used?
12 Were the economic model (including structure), study methods and analysis, and the components of the numerator and denominator displayed in a clear transparent manner?
13 Were the choice of economic model, main assumptions and limitations of the study stated and justified?
14 Did the author(s) explicitly discuss direction and magnitude of potential biases?
15 Were the conclusion/recommendations of the study justified and based on the study results?
16 Was there a statement disclosing the source of funding for the study?
Fig. 1 Flow chart of the study selection process using a 31-health-state Markov model [43], one study conducted CEA using a 5-year cohort-based Markov model [44], one study conducted CEA using a 1-year cycle cohort-based Markov state transition model [45], one study conducted CEA using a lifetime Markov model [46], five studies conducted CEA [2,[47][48][49][50], two studies conducted both CEA and CBA [10,51], one study conducted CEA using simulation model [52], one study conducted CEA using a treatment-sequence model [53], one study conducted CUA and budget impact analysis (BIA) using a Markov state transition model [54], one study conducted CEA using a published Markov structure with health states based on the Expanded Disability Status Scale (EDSS) [55], one study conducted CEA using a Markov state transition model [56], one study conducted CEA using a Markov economic model [57], five studies conducted CEA using a cohort Markov economic model [10,13,17,51,58], one study conducted CEA using a microsimulation model [19], one study conducted CEA using a discrete-time Markov model [59], one study condcuted CEA using a cohort-based multi-state Markov model [60], and one study conducted CEA using a probabilistic Markov model (second-order Monte Carlo simulation) [61] (Table 2).
One study was conducted from the UK societal cost perspective [22], two from UK National Health Service [2,58], one from UK third-party payer perspective [55], two from Canadian healthcare system perspective [13,59], one from Chilean health care public sector perspective [38], one from Kingdom of Saudi Arabia payer's perspective [56], two from Payer perspective [34,45], one from the Colombian healthcare system perspective [57], one from Italian societal perspective [28], one from Italian National Healthcare System perspective [60], one study from Swiss health insurance perspective [30], one from Payer and societal perspective [17], eleven studies from societal perspective [19, 27, 29, 31-33, 35, 42-44, 51], three studies from Ministry of Health perspective [50,52,64], one from Third-party payer perspective [23], one from Saudi payer perspective [24], two from US payer perspective [18,37], one from US health care payer perspective [47], one from both National Health Service and Personal Social Services perspective [25], two from Spanish National Health System [39,61], one from thirdparty payer perspective [63], one from both patients and third-party payers perspective [26], one from healthcare perspective [36], one from public healthcare perspective [49], one from both National Health Service and Personal Social Services perspective [41], one from both thirdparty payer & Societal [46], and one from Finnish payer perspective and Scenario analysis with a societal perspective [10], one from both health economics and societal perspective [53], one from Lebanese National Social Security Fund (NSSF) perspective [54], and one from both healthcare sector & societal perspective [40].

Quality of included studies
The studies included in the literature review were of variable quality (Table 2).Forty-four studies were graded high, 2 were thought to be fair and 1 was poor.
The proportion of studies that met the criteria for reporting of economic evaluations used in the quality index tool is shown in Table 3.
All the studies expounded their purpose clearly, and economic evaluation was the primary objective the most included studies.Most of them calculated costs appropriately and made a straightforward description of the methodology used.Most of the studies gave details of the economic model used and of the numerator and denominator components of the ICER, and also reported incremental cost and incremental cost-effectiveness ratio (ICERs) per different natural units particularly the quality of life years (QALYs).Most of them justified their conclusions based on the results obtained.The study perspective was stated in all articles except for one study did not.Most of them provided a justification for the discount rate.Also, most of the studies disclosed their funding sources except for seven studies did not.

Outcome and cost estimates
Most of the included studies reported incremental cost and incremental cost-effectiveness ratio (ICERs) per different natural units particularly the quality of life years (QALYs).The numerical value of outcome measures ranged from -1,623,918 to 2,297,141.53.In a study by Sawad et al., the lowest numerical value was related to the comparison of strategies 4 (symptom management (SM) and alemtuzumab) and 3 (SM and natalizumab), and the highest numerical value was related to the comparison of strategies 2 (symptom management (SM) and IFN-β-1a) and 1 (SM alone) [63].In a study conducted in Italy, the highest value for the total lifetime cost per patient treated with IFN beta-1b-250 mcg was $1,474,840.19 [42], Table 4.

The incremental cost-effectiveness ratio of the included studies
As the outcomes and protocols of each study were too heterogeneous to allow a statistical analysis of grouped data, we presented the results using a descriptive analysis approach (Table 4).Ten studies analyzed the first line of treatment [10,24,27,35,42,47,48,51,55,64], three studies looked at both first-and second-line treatment [13,17,53], and two studies focused on first-, second-and third-line treatment [19,63].One study looked at both first-and second-line treatment of RRMS as well as first-line treatment of PPMS [37].One study looked at for the treatment of both RMS and PPMS [33].Moreover, Table 3 Proportion of studies that met the selected criteria for grading economic evaluations Questions N 1 Was the study objective presented clearly and in a measurable manner?49 Were the perspective of the analysis (health system, third-party payer, etc.) and reason for its selection stated?48 Were variable estimates used in the analysis from the best available source (i.e.randomized control trial-best, expert opinion-worst)?37 If estimates came from a subgroup analysis, were the groups prespecified at the beginning of the study?49 5 Was uncertainty handled by: (1) statistical analysis to address random events; (2) sensitivity analysis to cover a range of assumptions?47 6 Was incremental analysis performed between alternatives for resources and costs?43 Was the methodology for data abstraction (including the value of health states and other benefits) stated?45 8 Did the analytic horizon allow time for all relevant and important outcomes?Were benefits and cost that went beyond 1 year discounted and a justification given for the discount rate?46 9 Was the measurement of costs appropriate and the methodology for the estimation of quantities and unit costs clearly described?43 10 Were the primary outcome measure(s) for the economic evaluation clearly stated and were the major short-term, long-term, and negative outcomes included?47 11 Were the health outcomes measures/scales valid and reliable?If previously tested, valid and reliable measures were not available, was justification given for the measures/scale used?

Interferon betas
The estimates with a 20-year time horizon were markedly lower, ranging from £42 000 to £98 000 per QALY gained ---
According to Mantovani et al., Su et al. and Zhang et al. [42,51,64] dimethyl fumarate was more cost-effective and was associated with higher QALYs and YLs as compared with IFN beta-1a -22 &44 mcg, IFN beta-1b -250 mcg, interferon-b 1a, interferon-b 1b, glatiramer acetate and teriflunomide, Rebif, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and intramuscular interferon-b1a.Chanatittarat et al. demonstrated although fingolimod was not the most cost-effective treatment, it was associated with higher QALYs and LYs [35].Alsaqa'aby et al., evaluated cost-effectiveness of oral agents (fingolimod, teriflunomide, dimethyl fumarate) in RRMS compared to interferon-based therapy (Avonex and Rebif ) in Saudi Arabia and showed Rebif was an optimal therapy at a WTP threshold of $100 000.They reported although Avonex had the lowest ICER value of $337 282/QALY when compared to Rebif, it was not costeffective at acceptable universal WTP thresholds [24].
Spelman et al. showed natalizumab dominated fingolimod (higher QALYs and lower costs) for UK patients inadequately responding to first-line (interferon-based therapies, glatiramer acetate, dimethyl fumarate, and teriflunomide (BRACETD)).They also showed switching to natalizumab was associated with a significant reduction in annualized relapse rate and an increase in improvement (CDI6M) compared to switching to fingolimod [55].According to Kantor et al. in the US, treatment with ozanimod was associated with considerable reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with fingolimod, dimethyl fumarate, and teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate.In other words, treatment with ozanimod was associated with annual healthcare cost savings ranging from $2178 (vs fingolimod) to $8257 (vs interferon beta-1a 30 μg) [48].Russell et al. showed intramuscular interferon beta-1a was more cost-effective than subcutaneous interferon beta-1a, interferon beta-1b, and glatiramer acetate [47].Dembek et al. showed interferon beta-1a was more costeffective and yielded greater QALY than subcutaneous interferon beta-1a, interferon beta-1b, glatiramer acetate and best supportive care [27].
According to Zimmermann et al. ocrelizumab dominated the other DMTs (dimethyl fumarate, glatiramer acetate, interferon β-1a, interferon β-1b, peginterferon β-1a, teriflunomide, natalizumab, fingolimod) with an ICER of US$166,338/QALY compared with supportive care and can be cost-effective as a first-line treatment for RRMS with a discounted price.They also reported ocrelizumab, peginterferon β-1a, and natalizumab added more QALYs, but at higher costs than other DMTs [37].Smets et al., in the Netherlands showed for first-line treatment although ocrelizumab did come at a higher cost than treatment with ofatumumab, it yielded more QALYs than ofatumumab, and ofatumumab was better in prevention of relapses for first-or secondline treatment [53].According to Baharnoori et al. in Canada ofatumumab was dominant (more effective, lower costs) compared with teriflunomide, interferons, dimethyl fumarate, and ocrelizumab, and ofatumumab resulted in ICERs of $24,189 Canadian dollars per QALY and $28,014/QALY compared with glatiramer acetate and best supportive care, respectively [13].
Furneri et al. evaluated cost-effectiveness of early escalation to natalizumab vs. switching among immunomodulators, and late escalation to natalizumab, in patients with RRMS in Italy who have failed first-line treatment with either interferon beta or glatiramer acetate.They showed that early escalation to natalizumab in RRMS patients who do not respond adequately to conventional immunomodulators (interferon beta, glatiramer acetate) led to both clinical and economic benefits, compared to switching among immunomodulators (interferon beta, glatiramer acetate) [28].In contrast, Ayati et al. in Iran demonstrated ocrelizumab was a more cost-effective option in terms of QALYs and YLg than natalizumab in patients with RRMS who failed to respond to at least one first-line DMT [43].

Second-line medications
Smet et al. compared differences in benefits between anti-CD20 mAbs in the Netherlands from a health-economic and societal perspective.They showed although drug sequences with ocrelizumab in second-line therapy were more cost-effective (higher cost but more QALYs) than ofatumumab, this outcome was very uncertain, according to the probabilistic analysis [53].
Baharnoori et al. evaluated the cost-effectiveness of ofatumumab from a Canadian healthcare system perspective, and showed ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine [13].According to Zimmermann et al. for RRMS second-line therapy, alemtuzumab dominated natalizumab, fingolimod, and ocrelizumab, and was associated with more QALYs and lower costs [37].

Third-line medications
Sawad et al. compared four strategies; symptom management (SM) alone, SM in combination with one of the following: IFN-β-1a, natalizumab (after switching from IFN-β-1a) and alemtuzumab (after using IFNβ-1a, then switching to natalizumab) in the US.They showed although none of the DMTs were cost-effective with respect to the threshold (threshold of USD 50,000-100,000), alemtuzumab dominated over natalizumab, regardless of the WTP per QALY threshold [63].Versteegh et al. (5W) focused on three line treatments and compared 360 treatment escalation sequences for patients with RRMS in terms of health outcomes and societal costs in the Netherlands.They showed optimal lifetime health outcomes were achieved with the sequence peginterferon, dimethyl fumarate, ocrelizumab, natalizumab and alemtuzumab.The most cost-effective sequence (peginterferon-glatiramer acetate-ocrelizumab-cladribine-alemtuzumab) yielded numerically worse health outcomes per patient but resulted in less costs than the most effective treatment sequence [19].

DMDs in HAD RRMs patients
Eight studies evaluated the cost-effectiveness of cladribine tablets in HDA RRMs patients.
A study in Lebonan demonstrated cladribine tablets were a cost-effective (less costly and more effective in terms of QALY) and budget-saving treatment option for the treatment of HDA RMS patients when compared with alemtuzumab, fingolimod, and natalizumab [54].Similarly, Michels et al. in the Netherlands showed treatment of RRMS with cladribine tablets was cost-effective versus alemtuzumab and fingolimod in HDA patients, and cost-effective versus natalizumab in rapidly evolving severe (RES) patients, at a threshold of €50,000/QALY gained [32]. Bohlega et al. in Saudi Arabia showed cladribine tablets as a treatment option for patients with HDA compared with alemtuzumab, dimethyl fumarate, fingolimod, interferon beta-1a (subcutaneous and intramuscular) and beta-1b, natalizumab, and teriflunomide.Their analysis demonstrated cladribine tablets as dominant strategy (less costly and more effective in terms of QALY) [56].Poveda et al. in Spain compared the cost-effectiveness of cladribine tablets with fingolimod in patients with HDA and showed cladribine tablets were the dominant treatment (lower costs and higher QALYs) compared to fingolimod and could generate savings for the Spanish National Health System [39].Ayati et al., in Iran compared the cost-utility of cladribine tablets in patients with HDA-RMS with natalizumab, and showed cladribine tablets dominated natalizumab with lower cost and higher QALYs per patient [44].Pinheiro et al. assessed the cost-utility of cladribine tablets versus fingolimod in patients with highly active RRMS in Portugal.They showed cladribine tablets was less costly and more effective and also was associated with higher QALYs and a delay in progression than treatment with fingolimod [45].Ginestal et al. evaluated the cost-effectiveness treatment of RRMS with cladribine tablets and dimethyl fumarate in Spain.They showed cladribine tablets treatment was found to be a dominant treatment and was associated with lower costs and greater QALY compared with dimethyl fumarate [61].Conversely, a study in Chile demonstrated, that although cladribine was associated with better QALYs in HDA MS patients, it was not a cost-effective alternative compared with alemtuzumab, natalizumab, and ocrelizumab [38].
Moreover, 5 studies evaluated the cost-effectiveness of DMTs in patients with highly active RRMS [22,41,55,57].Stanisic et al. in Italy assessed the cost-effectiveness of alemtuzumab in comparison with subcutaneous IFN β-1a, natalizumab and fingolimod in management of RRMS.Thy showed alemtuzumab yielded more QALYs and less costs compared to the other DMTs, and carried the highest likelihood of being below the accepted WTP threshold (€40,000) compared to IFN β-1a, natalizumab and fingolimod.They also reported alemtuzumab can be considered as a preferable treatment option in the management of active or highly active RRMS [34].Gani et al. in the UK compared the cost-effectivness of natalizumab with other DMTs (interferon-β, glatiramer acetate and best supportive care) and showed natalizumab was a cost-effective treatment and was associated with higher QALY for all patients with highly active RRMS (HAR-RMS) [22].Spelman et al. in the UK in a comparative effectiveness analysis showed switching to natalizumab improves clinical and economic outcomes relative to switching to fingolimod in patients with HA-RRMS with inadequate response to BRACETD, and results in higher QALYs and lower costs [55].Lasalvia et al. evaluated the cost-effectiveness of natalizumab compared with fingolimod for treating highly active RRMS patients in Colombia with failure of first-line therapy with interferons and showed natalizumab dominated fingolimod with lower costs and higher QALYs [57].Conversely, one study in the UK demonstrated fingolimod was a cost-effective treatment and was associated with higher QALYs than dimethyl fumarate in HAD patients [41].Cost, QALY, threshold and ICER values of all included studies are presented in Table 4.

DMTs in patients with PPMS & SPMS
One study evaluated the cost-effectiveness of ocrelizumab versus supportive care for first-line treatment of PPMS [37].One study evaluated the cost-effectiveness of ocrelizumab versus supportive care for the treatment of PPMS and versus interferon β-1a, dimethyl fumarate, glatiramer acetate, teriflunomide, fingolimod, and natalizumab for the treatment of RMS [33].Three studies [30,58,60] evaluated the cost-effectiveness of siponimod versus other DMTs in patients with SPMS.
Montgomery et al., in the UK evaluated the costeffectiveness of oral siponimod versus continued oral or infused RRMS DMTs (natalizumab, ocrelizumab, fingolimod, dimethyl fumarate, teriflunomide) for patients with active SPMS.They showed siponimod was more cost-effective, yielded greater QALYs and offered a clinically beneficial treatment approach compared with the continuation of oral or infused RRMS DMTs [58].Schur et al. evaluate the cost-effectiveness and budget impact of siponimod compared to interferon beta-1a for adult patients with SPMS with active disease.They showed siponimod may be cost-effective and yeilds more QALYs and YLs for treating Swiss adult patients with SPMS with active disease [30].Cortesi et al. estimated the siponimod cost-effectiveness profile and its relative budget impact compared with interferon beta-1b for patients with SPMS.They showed siponimod resulted in the most effective treatment (more QALY) but also more expensive compared with interferon beta-1b [60].Zimmermann et al. in the US demonstrated, for PPMS, ocrelizumab had an ICER of US$648,799/QALY compared with supportive care but was not cost-effective for PPMS [37].A study by Martins et al. in Portugal demonstrated ocrelizumab could provide important health benefits as a therapy for both RMS and PPMS.Ocrelizumab was among the most effective treatment options for RMS patients compared with other DMTs and compared with BSC for PPMS patients and yielded more LYs and QALYs for RMS and PPMS patients [33].

Discussion
We systematically reviewed the literature with the objective of analyzing recent published evidence on cost-utility and cost-effectiveness of DMDs for RRMS.To the best of our knowledge it is the first systematic review to examine the cost-ctility and cost-cffectiveness of DMDs for RRMS.
In this review ICER values exhibited a broad variability, even within one same treatment and using the same control medication.This variability can be due to the parameters selected to develop the pharmacoeconomic model, and /or the WTP per QALY threshold established.
Concerning interferon Beta, studies showed that interferon Beta (e.g.interferon beta-1b) can reduce reduce lifetime disability years by 10% [52] and is associated with an improved effectiveness compared with preventive treatment [46].Additionally, the cost-effectivness of peginterferon beta-1a was studied in the US and Iran [18,25,26].They demonstrated peginterferon beta-1a was a cost-effective strategy and was associated with lower cost and more QALY compared with interferon beta-1a, interferon beta-1b and glatiramer acetate in the treatment of RRMS.
Ten studies [13,19,23,33,34,37,49,53,56,64] evaluated the cost-effectiveness of all three forms of DMDs for RRMS, the oral DMDs.The results varied between studies.The difference in the results can attributed to several factors such as the patients selection criteria, age groups studied, medications studied, availability of drugs in each country, treatment line, setting, disease severity, demographic and socio-economic determinants measured.Eleven studies [10,17,24,30,35,42,48,51,59,60,64] evaluated the cost-effectiveness of injectable and oral DMDs for RRMS and reported oral drugs were more cost-effective than injectable drugs.Likewise, eight studies [32,38,40,44,54,55,57,58] evaluated the costeffectiveness of oral and intravenous infusions DMDs of RRMS, of which 5 studies reported oral drugs were more cost-effective than intravenous infusions DMDs.In general, oral medications are preferred by patients to other forms of medication due to their being non-invasive nature.
In two studies, the cost-effectiveness of injectable drugs and intravenous infusions was analyzed by symptom management.In both studies, symptom management was more cost-effective and was associated with higher QALYs and YLs when compared with IFN-β-1a, natalizumab, alemtuzumab, glatiramer acetate subcutaneous, and intramuscular interferon β-1b.This can be attributed to the lower cost of drugs and equipment [31,63].
For the second-line treatment, ofatumumab [13] and alemtuzumab [37] were found to be more cost-effective and yielded more QALY.Smets et al. showed although treatment with ocrelizumab was associated with higher cost than that of ofatumumab, it yielded more QALY than ofatumumab [53].
Of 8 studies that evaluated the cost-effectiveness of cladribine tablets in HDA patients, 7 studies demonstrated cladribine tablets were a cost-effective option (less costly and greater QALY) compared with alemtuzumab, fingolimod, natalizumab, dimethyl fumarate, interferon beta-1a (subcutaneous and intramuscular), beta-1b, natalizumab, and teriflunomide in HDA patients [32,39,44,45,54,56,61].Previous systematic reviews and meta-analyses also demonstrated that cladribine tablets can be an effective and safe drug and an alternative to other DMTs in achieving better treatment for RRMS, active RRMS and for a subgroup with high disease activity (HRA + DAT) populations [65,66].This can be due to the oral posology of cladribine tablets where the treatment effect is expected to last for up to 4 years with only 2 years of treatment [67].This drug has no costs of administration and lower monitoring costs compared to other drugs.Also, induction therapies, such as cladribine have low discontinuation rates owing to the prearranged schedule for treatment administration [13].
Considering DMTs in HAD patients, 3 studies demonstrated natalizumab was a cost-effective treatment and was associated with higher QALY as compared with interferon-β, glatiramer acetate, best supportive care and fingolimod [22,55,57].It seems natalizumab can be considered as a cost-effective treatment in HDA patients.
Considering the cost-effctivness of siponimod versus other DMTs in patients with SPMS, studies conducted in the UK, Switzerland and Italy demonstrated siponimod was more cost-effective and yielded greater QALYs [30,58,60] and YLs [30] for treating patients with SPMS with active disease when compared with natalizumab, ocrelizumab, fingolimod, dimethyl fumarate, teriflunomide [58], interferon beta-1a [30] and interferon beta-1b [60].Moreover, studies in this review demonstrated ocrelizumab can provide important health benefits as a therapy for RMS and PPMS patients compared with supportive care, yielding more LYs and QALYs [33,37].A previous systematic review and network meta-analysis compared ocrelizumab with other treatments for RMS and demonstrated the efficacy and safety of ocrelizumab in a direct comparison with interferon β-1a 44 μg (Rebif 44 mg) [68].This medication was approved by the US Food and Drug Administration in March 2017 and by the European Medicines Agency in January 2018 for the treatment of RMS and PPMS [68].
In this review, 3 studies evaluated the cost-effectiveness of rituximab and showed RRMS patients receiving rituximab had lower costs and more QALYs when compared with natalizumab [29,62].Smet et al. in the Netherlands suggested rituximab would already be the most cost-effective anti-CD20 mAb if its efficacy on 6-month CDP is comparable to traditional first-line therapies such as interferon-beta but there are no accurate estimates of rituximab's effect on disability progression [53].Although rituximab has not yet been approved by the United States Food and Drug Administration (USFDA) for treating MS, it has been used extensively as an off-label medication for MS control and management.Moreover, rituximab has shown more efficacy in managing RRMS when compared with fingolimod and a better safety profile than natalizumab [69,70].Nonetheless, some studies have shown that the use of rituximab, natalizumab, ocrelizumab, interferons, or other injectable DMTs is associated with higher rates of nonadherence in MS managment among patients, especially those with chronic health conditions [71,72].

Limitations
Our review has some limitations.First, our review was limited to English and Persian language publications, and there is a chance of publication bias.So future reviews should include additional languages, if feasible.Second, several studies in this review received funding from pharmaceutical or biotechnology companies.Industry sponsorship can be a source of bias as they may support a particular agenda and be influential at multiple stages of research design and implementation and influence the choice of research priorities [73].Third, the included studies were from different countries which have varied healthcare systems which effects the overall bias of the review.

Conclusions
We found that, of the evaluated DMTs, cladribine tablets and natalizumab were the optimal choices for patients with highly active RRMS.Siponimod was also found to be a cost-effective option for patients patients with SPMS.Among the drug strategies with different prescribing methods, oral DMDs for RRMS should be preferred to injectable drugs and intravenous infusions for various reasons such as their non-invasiveness and greater convenience for patients, and lower cost.This review showed that care-oriented strategies such as BSC and SM strategies should be preferred to drug strategies and be considered a valuable early treatment option for patients with RRMS.
Of note, the outcomes of a cost-effectiveness analysis frequently exhibit country-specific characteristics since treatment and healthcare costs data can diverge substantially across nations.Moreover, it is noteworthy that incremental costs and QALYs may vary between different settings, even if the same fundamental modeling approach is employed.Although studies show MS is a costly disease, cost estimates vary between nations.Therefore, health policy makers, neurologists, and other involved parties should base their decisions on local findings with regards to the financial burden caused by MS and the cost-effectiveness of DMTs.
β-1a, fingolimod led to an increase in QALYs with incremental costs and to an ICER of CAD 23,886/QALY over a time horizon of two years

Table 1
The quality of health economic studies (QHES) instrument

Table 4
Outcomes and Costs of included studies